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. 2016 Apr 27:7:11375.
doi: 10.1038/ncomms11375.

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Fergus J Couch  1   2 , Karoline B Kuchenbaecker  3 , Kyriaki Michailidou  3 , Gustavo A Mendoza-Fandino  4 , Silje Nord  5 , Janna Lilyquist  2 , Curtis Olswold  2 , Emily Hallberg  2 , Simona Agata  6 , Habibul Ahsan  7   8   9 , Kristiina Aittomäki  10 , Christine Ambrosone  11 , Irene L Andrulis  12   13 , Hoda Anton-Culver  14 , Volker Arndt  15 , Banu K Arun  16 , Brita Arver  17 , Monica Barile  18 , Rosa B Barkardottir  19 , Daniel Barrowdale  3 , Lars Beckmann  20 , Matthias W Beckmann  21 , Javier Benitez  22   23   24 , Stephanie V Blank  25 , Carl Blomqvist  26 , Natalia V Bogdanova  27 , Stig E Bojesen  28 , Manjeet K Bolla  3 , Bernardo Bonanni  18 , Hiltrud Brauch  29   30 , Hermann Brenner  15   31 , Barbara Burwinkel  32 , Saundra S Buys  33 , Trinidad Caldes  34 , Maria A Caligo  35 , Federico Canzian  36 , Jane Carpenter  37 , Jenny Chang-Claude  38 , Stephen J Chanock  39 , Wendy K Chung  40 , Kathleen B M Claes  41 , Angela Cox  42 , Simon S Cross  43 , Julie M Cunningham  1 , Kamila Czene  44 , Mary B Daly  45 , Francesca Damiola  46 , Hatef Darabi  44 , Miguel de la Hoya  34 , Peter Devilee  47 , Orland Diez  48 , Yuan C Ding  49 , Riccardo Dolcetti  50 , Susan M Domchek  51 , Cecilia M Dorfling  52 , Isabel Dos-Santos-Silva  53 , Martine Dumont  54 , Alison M Dunning  55 , Diana M Eccles  56 , Hans Ehrencrona  57   58 , Arif B Ekici  59   60 , Heather Eliassen  61   62 , Steve Ellis  3 , Peter A Fasching  21 , Jonine Figueroa  39 , Dieter Flesch-Janys  63 , Asta Försti  64   65 , Florentia Fostira  66 , William D Foulkes  67 , Tara Friebel  68 , Eitan Friedman  69 , Debra Frost  3 , Marike Gabrielson  44 , Marilie D Gammon  70 , Patricia A Ganz  71 , Susan M Gapstur  72 , Judy Garber  73 , Mia M Gaudet  72 , Simon A Gayther  74 , Anne-Marie Gerdes  75 , Maya Ghoussaini  55 , Graham G Giles  76 , Gord Glendon  12 , Andrew K Godwin  77 , Mark S Goldberg  78   79 , David E Goldgar  80 , Anna González-Neira  81 , Mark H Greene  82 , Jacek Gronwald  83 , Pascal Guénel  84 , Marc Gunter  85 , Lothar Haeberle  21 , Christopher A Haiman  86 , Ute Hamann  87 , Thomas V O Hansen  88 , Steven Hart  2 , Sue Healey  89 , Tuomas Heikkinen  32   90 , Brian E Henderson  86 , Josef Herzog  91 , Frans B L Hogervorst  92 , Antoinette Hollestelle  93 , Maartje J Hooning  94 , Robert N Hoover  39 , John L Hopper  95 , Keith Humphreys  44 , David J Hunter  96 , Tomasz Huzarski  83 , Evgeny N Imyanitov  97 , Claudine Isaacs  98 , Anna Jakubowska  83 , Paul James  99   100 , Ramunas Janavicius  101 , Uffe Birk Jensen  102 , Esther M John  103 , Michael Jones  104 , Maria Kabisch  87 , Siddhartha Kar  55 , Beth Y Karlan  105 , Sofia Khan  106 , Kay-Tee Khaw  107 , Muhammad G Kibriya  7 , Julia A Knight  108 , Yon-Dschun Ko  109 , Irene Konstantopoulou  66 , Veli-Matti Kosma  110 , Vessela Kristensen  5 , Ava Kwong  111   112 , Yael Laitman  69 , Diether Lambrechts  113 , Conxi Lazaro  114 , Eunjung Lee  115 , Loic Le Marchand  116 , Jenny Lester  105 , Annika Lindblom  117 , Noralane Lindor  118 , Sara Lindstrom  62   119 , Jianjun Liu  120 , Jirong Long  121 , Jan Lubinski  83 , Phuong L Mai  82 , Enes Makalic  95 , Kathleen E Malone  122   123 , Arto Mannermaa  110 , Siranoush Manoukian  124 , Sara Margolin  17 , Frederik Marme  32 , John W M Martens  93 , Lesley McGuffog  3 , Alfons Meindl  125 , Austin Miller  126 , Roger L Milne  76 , Penelope Miron  127 , Marco Montagna  6 , Sylvie Mazoyer  46 , Anna M Mulligan  128   129 , Taru A Muranen  32   90 , Katherine L Nathanson  51 , Susan L Neuhausen  49 , Heli Nevanlinna  106 , Børge G Nordestgaard  28 , Robert L Nussbaum  130 , Kenneth Offit  131 , Edith Olah  132 , Olufunmilayo I Olopade  133 , Janet E Olson  2 , Ana Osorio  22 , Sue K Park  134 , Petra H Peeters  135   136 , Bernard Peissel  124 , Paolo Peterlongo  137 , Julian Peto  53 , Catherine M Phelan  4 , Robert Pilarski  138 , Bruce Poppe  41 , Katri Pylkäs  139 , Paolo Radice  140 , Nazneen Rahman  141 , Johanna Rantala  142 , Christine Rappaport  143 , Gad Rennert  144 , Andrea Richardson  145 , Mark Robson  131 , Isabelle Romieu  146 , Anja Rudolph  38 , Emiel J Rutgers  147 , Maria-Jose Sanchez  148   149 , Regina M Santella  150 , Elinor J Sawyer  151 , Daniel F Schmidt  95 , Marjanka K Schmidt  147 , Rita K Schmutzler  152   153   154 , Fredrick Schumacher  86 , Rodney Scott  155 , Leigha Senter  138 , Priyanka Sharma  156 , Jacques Simard  157 , Christian F Singer  143 , Olga M Sinilnikova  46   158 , Penny Soucy  157 , Melissa Southey  159 , Doris Steinemann  160 , Marie Stenmark-Askmalm  161 , Dominique Stoppa-Lyonnet  162   163 , Anthony Swerdlow  104 , Csilla I Szabo  164 , Rulla Tamimi  61   62   119 , William Tapper  56 , Manuel R Teixeira  165   166 , Soo-Hwang Teo  167   168 , Mary B Terry  169 , Mads Thomassen  170 , Deborah Thompson  3 , Laima Tihomirova  171 , Amanda E Toland  172 , Robert A E M Tollenaar  173 , Ian Tomlinson  174 , Thérèse Truong  84 , Helen Tsimiklis  159 , Alex Teulé  175 , Rosario Tumino  176 , Nadine Tung  177 , Clare Turnbull  141 , Giski Ursin  178 , Carolien H M van Deurzen  179 , Elizabeth J van Rensburg  52 , Raymonda Varon-Mateeva  180 , Zhaoming Wang  181 , Shan Wang-Gohrke  182 , Elisabete Weiderpass  44   178   183   184 , Jeffrey N Weitzel  91 , Alice Whittemore  185 , Hans Wildiers  186 , Robert Winqvist  139 , Xiaohong R Yang  187 , Drakoulis Yannoukakos  66 , Song Yao  11 , M Pilar Zamora  188 , Wei Zheng  121 , Per Hall  44 , Peter Kraft  62   119   189 , Celine Vachon  2 , Susan Slager  2 , Georgia Chenevix-Trench  190 , Paul D P Pharoah  55 , Alvaro A N Monteiro  4 , Montserrat García-Closas  191 , Douglas F Easton  3 , Antonis C Antoniou  3
Affiliations

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Fergus J Couch et al. Nat Commun. .

Abstract

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

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Figures

Figure 1
Figure 1. Manhattan plot of ER-negative breast cancer meta-analysis.
The Manhattan plot displays the strength of genetic association (−log10 P) versus chromosomal position (Mb), where each dot presents a genotyped or imputed (black circle) SNP. The black horizontal line represents the threshold for genome-wide significance (P=5 × 10−8).
Figure 2
Figure 2. Novel ER-negative breast cancer loci.
The chromosomal position and strength of genetic association (−log10 P) is shown for all SNPs (P<1 × 10−6) in BCAC/iCOGS data in the four novel risk loci. (a). 2p23 locus. The most significant SNP (rs67073037) is shown as a diamond. (b). 13q22 loci. The most significant SNP (rs6562760) is shown as a diamond. The second locus is shown in black. (c). 2q33 locus. The most significant SNPs (rs188686860; rs115635831) are shown as diamonds.
Figure 3
Figure 3. The chromatin landscape of locus 2p23.2.
(a) The SNP rs4407214 is included in a genomic tile overlapping chromatin features indicative of promoters and enhancers, shaded red. (b,c). Luciferase assays showing activity in the tile containing SNP rs4407214 (highlighted in pink in a.) in MCF10A and CAL51, red box plots indicate significantly different from the control tile (P<0.0001). Brown box plot indicates significant difference from the reference allele (P= 0.0059). (d) Electrophoretic mobility shift assay (EMSA) showing the formation of allele-specific complexes for rs4407214. M, major allele; m, minor allele. Lines 1, 2, 7, 8—no nuclear extract. Lines 3, 4, 5, 6—10 μg of MCF10A nuclear extract. Lines 9, 10, 11, 12—10 μg of CAL51 nuclear extract. Shift detected by comparison to bands (arrows #1 and #2).
See this image and copyright information in PMC

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